1, 1&#39;-(hexafluoroglutaryl)-bis(4-phenylpiperazine)



United States Patent tion of Maine No Drawing. Filed Oct. 20, 1959, Ser. No. 847,461

- 1 Claim. (Cl. 260-268) This invention relates to an improved process of preparing halogenated alkanoylpi-perazines. More particularly, it relates to the process of reacting lower alkyl esters of halogenated alkanoic acids with substituted piperazines.

The group of compounds broadly classifiable as halogenated alkanoylpiperazines have been found useful in several ditferent fields. The mono and dihaloacetylpiper-azines such as described and claimed in U.S. Patent 2,807,617 are useful in treating hookWorrn infections While at the same time being relatively non-toxic to the host. The trihaloacetyl piperazines which are described and claimed in U.S. Patent 2,909,524 are highly active in the treatment of haemonchosis in animals. Improved methods of preparing these compounds are therefore highly desirable.

Conventionally, piperazines have been acylated Wit-h halo and polyhaloalkanoyl halides and anhydrides. These latter reagents, however, are corrosive, irritating, unstable, and generally diflicult to work with. The esters of the halo and polyhaloalkanoic acids of this invention, however, are cheaper, less corrosive, less irritating, and more stable. The improved process of this reaction not only avoids the difiiculties suggested above, but is more convenient and atiords higher yields of the product amides.

Furthermore, use of the esters by the method of this invention obviates the need for a solvent, although one can be used, and does not require use of an acid binder to take up the acid that is generated when acid anhydrides and acid chlorides are employed. Finally, the stoichimetry of the present method is more favorable.

The process of the present invention can be illustrated by the following equation.

CH -CH2 in which R is a phenyl, lower alkylphenyl, halophenyl, carboloweralkoxy or heterocyclic radical, R is a lower alkyl radical, X is a halogen radical, Z is hydrogen, halogen or a carboloweralkoxy radical, n is a whole integer from 1 to 8 and Y is hydrogen or a halogen or a radical.

The substituted piperazines used as starting material can be for example l-phenylpiperazine, l-(2,6-Xylyl) piper-azine, l-(m-chlorophenyl)piperazine, l-(p-chlorophenyl)piperazine, l-carbethoxypiperazine, l-car-biso-butoxypiperazine, l-(p-bromophenyl)piperazine, 1- (mbrornophenyl.)piperazine, 1-(2-pyrimidinyl)piperazine, l- (2-pyridyl)piperazine, l-(2-thiazolyl)piperazine, 1-(3- pyridazinyl)piperazine, and the like.

The lower alkyl esters of halogenatel alkanoic acids can be for example, ethyl chlorodifiuoroacetate, ethyl ice fluorodichloroacetate, ethyl trifluoroacetate, ethyl difiuoroacetate, ethyl dichloroacetate, methyl dichloroa tate, ethyl heptafiuo-robutyr-ate, ethyl pentadecailuorooctanoate, ethyl hexafiuoroglutarate, ethyl hexachloroglutarate and the like.

Usually the reaction of the present invention is carried out Without the use of a solvent. The two reactants are preferably mixed together in stoichiometric amounts or, in the case of more vigorous reactants, one is added slowly to the other. During mixing or addition, cooling may be required, and on the other hand after mixing or addition, warming may be desirable to complete the reaction. the alcohol produced gives the product as a residue. The product can also be recovered from the reaction mixture by filtration following the adding of a diluent. Generally, the reaction is carried out within a temperature range of 20-l10 C. The reaction is usually complete within a period of 10 minutes to several hours depending upon the temperature used.

The compounds prepared by the process of the present invention are useful in treating parasites or helminths in animals. These parasites are for example, Haemonchus in cattle or sheep, Ostertagia in cattle or sheep, Oesophagostomum in sheep or cattle, Bunostomum in sheep, Nematodir-us in sheep, Dictyoca-ulus in cattle, Metastrongylus in swine.

The following examples illustrate in detail the preparation of representative halogenated alkanoylpiperazines.

EXAMPLE I Preparation of 1-Phenyl-4-Ch0lorodifluoroacetylpiperazine EXAMPLE II Preparation of 1-Phenyl-4-Trifluoroacetylpiperazine To 31.3 g. of ethyl trifluoroacetate is added dropwise, with stirring, 32.4 g. of l-phenylpiperazine during a 20 minute period at 20-25 C. The solution is heated for l /zhours at 55 C. and is then concentrated under reduced pressure. The residue is slurried with petroleum ether (B.P. -100" C.) and the resulting solid removed by filtration to yield 50.2 g. of l-phenyl-4-trifluoroacetylpiperazine as colorless crystals. One recrystallization from aqueous ethanol raises the melting point to 6667 C.

EXAMPLE III Preparation of 1-Phenyl-4-Difluoroacelylpiperazine To 27.3 g. of ethyl difiuoroacetate is added dropwise, with a stirring, 32.4 g. of .l-phenylpiperazine during a 45 minute period at 20-25 C. A white precipitate begins to separate as soon as the amine addition has begun and 50 ml. of absolute ethanol is added to the mixture to give a clear solution. The solution is heated at 55- 60 C. for one hour and then concentrated under reduced pressure to yield 48.1 g. of a purple solid, melting point 45 60 C. Recrystallization of this solid from aqueous ethanol gives 33.4 g. of pale purple crystals of 1-phenyl-4-difiuoroacetylpiperazine. Treatment with activated charcoal in aqueous ethanol yields 27.8 g. of colorless crystals, melting point 56-57 C.

After the reaction is complete evaporation of EXAMPLE IV Preparation of 1-(2,6-Xylyl)-4-Trifluoroacetylpiperazine To 1.92 g. of 1-(2,6-xylyl)piperazine is added 1.56 g. of ethyl trifluoroacetate and the resulting solution is heated for one hour at 55-60 C. Concentration of the reaction solution under reduced pressure yields 2.86 g. of 1-(2,6-xylyl)-4-trifluoroacetylpiperazine as a pale brown solid. One recrystallization from absolute ethanol yields colorless crystals, melting point 72.5-74.5 C.

EXAMPLE V Preparation of l-(m-Chlorophenyl)-4Trifluor0- acetylpiperazine To 1.99 g. of l-(m-chlorophenyl)piperazine is added 1.56 g. of ethyl trifiuoroacetate and the resulting solution is treated in the same manner as Example IV to yield 2.96 g. of l-(m-chlorophenyl)-4-trifluoroacetylpiperazine as pale brown crystals. One recrystallization from absolute ethanol gives colorless crystals, melting point 51.5-53.0 C.

EXAMPLE VI Preparation of 1-(p-Chlorophenyl)-4-Triflu0r0- acetylpiperazine To 1.96 g. of :1-(p-chlorophenyl)piperazine is added 1.56 g. of ethyl trifluoroacetate and the resulting solution is treated in the same manner as Example IV to yield 2.93 g. of 1-(p-chlorophenyl)-4-trifluoroacetylpiperazine as colorless crystals. One recrystallization from absolute ethanol raises the melting point to 100-101" C. 7

EXAMPLE VII Preparation of I-(Z-Pyrimidinyl)-4-Triflaoroacetylpiperazine To 1.64 g. of 1-(2-pyrimidinyl)piperazine is added 1.56 g. of ethyl trifluoroacetate and the resulting solution is treated in the same manner as Example IV to yield 2.59 g. of 1-(2-pyrimidinyl)-4-trifluoroacetylpiperazine as pale brown crystals. One recrystallization from absolute ethanol gives colorless crystals, melting point 77.5-78.5 C.

EXAMPLE VIII Preparation of 1-(2-Pyridyl)-4-Triflu0r0acetylpiperazine To 1.63 g. of 1-(2-pyridyl)piperazine is added 1.56 g. of ethyl trifluoroacetate and the resulting solution is treated in the same manner as Example IV to yield 2.62 g. of l-(2-pyridyl)-4-trifluoroacetylpiperazine as pale brown crystals. Two recrystallizations from 50% ethanol gives colorless crystals, melting point 53-54 C.

EXAMPLE IX Preparation of I-Carbeth0xy-4-Triflu0r0aeetylpiperazine EXAMPLE X Preparation of 1-Carbis0but0xy-4-Triflu0r0acetylpiperazine To 1.87 g. of 1-carbisobutoxypiperazine is added 1.56 g. of ethyl trifiuoroacetate and the resulting solution is treated in the same manner as Example IV to yield 2.80 g. of l-carbisobutoxy-4-trifluoroacetylpiper-azine as pale yellow crystals, melting point 38-40 C.

EXAMPLE XI Preparation of 1-Phenyl-4-Heptaflaorobutyrylpiperazine Hydrochloride A solution of 53.3 g. of ethyl heptafiuorobutyrate in 25 ml. of ethanol is treated with 32.4 g. of l-phenylpiperazine at 20-25 C. and then heated on a steam bath for three hours. After concentration under reduced pressure, the residue is triturated with petroleum ether (RP. 30- 60 C.) and filtered to give 9.50 g. of colorless crystals of l-phenylpiperazine heptafluorobutyrate, melting point 115.8-1185 C. The filtrate is concentrated to dryness and the residue dissolved in ether. The ethereal solution is washed with sodium bicarbonate solution and water, after which it is treated with activated charcoal and dried over sodium sulfate. The addition of anhydrous hydrogen chloride then yields 51.7 g. of colorless crystals of l-phenyl 4 heptafluorobutyrylpiperazine hydrochloride, melting point l74-l80 C. Recrystallization from ethanol raises the melting point to 180-180.5 C.

EXAMPLE XII Preparation of 1-PlzenyZ-4-Pentadecaflu0rooczanoylpiperazine To 48.7 g. of ethyl pentadecafiuorooctanoate in 50 ml. of ethanol is added 16.2 g. of l-phenylpiperazine during a 40 min. periodat 20-25 C. The reaction solution is heated at 60-70 C. for one hour and then concentrated under reduced pressure to a brown solid, melting point 6l-65 C. Recrystallization from aqueous ethanol yields 27.5 g. of pale brown crystals. Repeated recrystallizations from ethanol yield 14.2 g. of l-phenyl-4-pentadecafluorooctanoylpiperazine as colorless crystals, melting point 78-79 C.

EXAMPLE XIII Preparation of 1,1'-(Hexaflaor0glataryl) bis (4-Phenylpiperazine) A solution of 3.24 g. of l-phenylpiperazine in 2.96 g. of ethyl hexafluoroglutarate is heated at 60-70 C. for one hour and is then concentrated under reduced pressure to a dark brown glass. Trituration of the residue with petroleum ether (B.P. -100 C.) and subsequent filtration yields 4.50 g. of pale brown crystals of 1,1- (hexafluoroglutaryl) bis 4-phenylpiperazine) Recrystallization from ethanol raises the melting point to 116.5- 117.5 C.

EXAMPLE XIV Preparation of J-Dichloroacetyl-4-Phenylpiperazine l-phenylpiperazine (12.15 kg.) and 10.68 kg. of methyl dichloroacetate are mixed and the temperature is allowed to rise to 65 C. before cooling is applied. Partial solidification occurs and 20 liters of alcohol is added to form a slurry. After standing overnight, the solid is removed by filtration, washed with three portions of alcohol and dried. The crude product is recrystallized from liters of alcohol to yield 10.9 kg. of l-phenyl-4-dichloroacetylpiperazine as colorless crystals, melting point 130-133 C.

EXAMPLE XV Preparation of 1-Dichloroacetyl-4-Phenylpiperazine To 40.5 g. of l-phenylpiperazine in 50 ml. of ethylene glycol is gradually added 53 g. of methyl dichloroacetate at 30-3l C. The mixture is stirred for two hours at 33-41 C. until the reaction is completed. The mixture is then treated with 150 ml. of cold water and after cooling to 12 C. the product is removed by filtration and washed with cold water to yield, after drying, 56.5 g. of a colorless, crystalline so-lid, melting point -126" C. Slurrying of the product with methanol followed by filtration and drying yields 49.2 g. of l-dichloroacetyllphenylpiperazine as colorless crystals, melting point 132 C.

5 EXAMPLE XVI Preparation of 1-Dichloroacetyl-4-Phenyl-Piperazine 7 melting point 129-1305" C.

We claim:

The compound 1,1'-(hexafluoroglutaryl)-bis(4-pheny1- piperazine).

References Cited in the file of this patent UNITED STATES PATENTS 2,483,885 Crooks et al. Oct. 4, 1949 2,807,617 Dalalian et al. Sept. 24, 1957 2,909,524 Dalalian et al. Oct. 20, 1959 OTHER REFERENCES Clermont: Compt. rend. (Fr. Acad. Sci), vol. 133, page 737 (1954).

Joullie et 21].: Jour. Am. Chem. 800., vol. 76, pages 2990-2993 (1954). 

